We have assembled a complementary team of basic cancer geneticists, mouse biologists, neuropathologists, neuro-oncologists, developmental neurobiologists, neurologists, and genomics-bioinformatics specialists to delineate the critical events in the genesis, progression and maintenance of malignant glioma. Malignant gliomas are aggressive, highly invasive and neurologically destructive tumors considered to be among the deadliest of human cancers. In its most aggressive manifestation, glioblastoma, median survival ranges from 9 to 12 months -- a fact that has changed little over several decades. It is indeed notable that, despite detailed knowledge of glioma-associated gene mutations, we know precious little about how such mutations contribute to the unique biology of this tumor type, whether such lesions play roles in both tumor genesis and maintenance, which cellular compartments serve as target for or origin of the transformation process, and why malignant gliomas remain refractory to existing therapy. It is our belief that the proposed studies will lead to meaningful insights that promise to validate specific mutations as essential or non-essential therapeutic targets as well as to identify biomarkers that will aide in glioma classification and ultimately clinical management. This new P01 application rests upon the hypotheses that: (1) genetic mutations involved in tumor genesis remain relevant to tumor maintenance; (2) tumor-associated genetic lesions play specific and discernable roles which relate to the unique biological features of glioma; and (3) genes/pathways controlling normal glia cell proliferation, survival and differentiation also contribute the pathogenesis of glioma. Drs. DePinho and Maher will exploit the experimental merits of the mouse to dissect how cellular differentiation and specific RTK and tumor suppressor gene mutations contribute to glioma progression and maintenance. Drs. Cavenee and Furnari will evaluate the genetic interactions of EGFR and PTEN through the com-bined use of expression profiling, genetic screens and cross-species model comparisons. Using neural stem cell technology and functional genomics, Drs. Rowitch and Bachoo will evaluate the role of key glioma-relevant mutations in the growth, survival and differentiation processes of normal glia. These projects will be aided by cores for Transgenic Mice and Neural Stem Cells (DePinho), Neuropathology (Louis), Genomics-Bioinformatics (Chin/Wong), and Administration (DePinho). The goals of this P01 mirror precisely the priorities articulated by the recent NCI/NINDS Brain Tumor PRG.